Background:Henoch-Schonlein purpura nephritis (HSPN) is a very common secondary kidney disease of childhood.Its pathogenesis and the treatment mechanism of glucocorticoid have not been fully elucidated.The aim of this study was to determine the relationship between p300 and the pathogenesis,glucocorticoid therapy in mice with HSPN,respectively.Methods:Forty-eight C57BL/6N male mice,weighing 18 to 20 g,were selected (3-4 weeks old,n =8 per group).The mice in the normal control group (Group Ⅰ) were given normal solvent and the HSPN model group (Group Ⅱ) were given sensitizing drugs.The mice in Group Ⅲ were injected intraperitoneally with dexamethasone after being given sensitizing drugs.Meanwhile,mice in Groups Ⅳ,Ⅴ and Ⅵ with conditional knockout of p300 were also given normal solvent,sensitizing drugs and dexamethasone.The levels of serum IgA,creatinine,and circulating immune complex (CIC) concentrations,24 h urinary protein and urinary erythrocyte in C57 wild mice,and p300 conditional knockout mice in each group were measured.The expression of p300 in renal tissues and the expression of glucocorticoid receptor (GR) α and β,transforming growth factor (TGF)-β1,and activator protein (AP)-1 after dexamethasone treatment were determined by real-time polymerase chain reaction and West blotting.Results:Compared with the normal solvent control group (Group Ⅰ),the expression of p300 mRNA in the model group (Group Ⅱ) was significantly up-regulated.West blotting further confirmed the result.Urinary erythrocyte count,24 h urinary protein quantification,serum IgA,CIC,and renal pathologic score in Group Ⅴ were distinctly decreased compared with non-knockout mice in Group Ⅱ (9.7±3.8 per high-power field [/HP] vs.18.7±6.2/HP,t=1.828,P=0.043;0.18±0.06g/24h vs.0.36 ± 0.08 g/24 h,t =1.837,P =0.042;18.78 ± 0.85 mg/mL vs.38.46 ± 0.46 mg/mL,t =1.925,P =0.038;0.80 ± 0.27 μg/mL vs.1.64 ± 0.47 μg/mL,t =1.892,P =0.041;7.0 ± 0.5 vs.18.0 ± 0.5,t=1.908,P =0.039).Compared with non-knockout mice (Group Ⅲ),the level of urinary erythrocyte count and serum IgA in knockout mice (Group Ⅵ) increased significantly after treatment with dexamethasone (3.7 ± 0.6/HP vs.9.2 ± 3.5/HP,t =2.186,P =0.024;12.38 ± 0.26 mg/mL vs.27.85 ± 0.65 mg/mL,t =1.852,P =0.041).The expression level of GRα was considerably increased in the knockout group after dexamethasone treatment compared with non-knockout mice in mRNA and protein level (t =2.085,P =0.026;t =1.928,P =0.035),but there was no statistically significant difference in the expression level of GRβ between condition knockout and non-knockout mice (t =0.059,P =0.087;t =0.038,P =1.12).Furthermore,the expression levds of glucocorticoid resistance genes (AP-1 and TGF-β1) were notably increased after p300 knockout compared with non-knockout mice in mRNA and protein level (TGF-β1:t =1.945,P =0.034;t =1.902,P =0.039;AP-1:t =1.914,P =0.038;t =1.802,P =0.041).Conclusions:p300 plays a crucial role in the pathogenesis of HSPN.p300 can down-regulate the expression of resistance genes (AP-1 and TGF-β1) by binding with GRα to prevent further renal injury and glucocorticoid resistance.Therefore,p300 is a promising new target in glucocorticoid therapy in HSPN.